ABSTRACT (Project 3. Clinical Trial) The future treatment for HAND will likely need to include both antiretroviral therapy and adjunctive therapy to treat central nervous system (CNS) specific pathogenetic mechanisms. Insulin is involved in multiple CNS functions including food intake, metabolism, learning, and memory. Insulin has neuroprotective properties demonstrated in cell culture experiments and in vivo models, which provide strong evidence for its use as a therapeutic agent to treat HAND. The brain delivery of insulin administered via a novel nasal drug delivery device has been shown to have CNS protective, restorative, and cognitive enhancing effects in over 15 independent clinical studies. In addition to standard neuropsychological testing, the proposed clinical trial will use several novel brain imaging and CSF surrogate markers to monitor the effects of intranasal insulin therapy in HAND patients. We will conduct a 24 week double-blinded, placebo-controlled Phase I/II trial of intranasal insulin for the treatment of HAND. Participants will be randomly assigned to one of two groups: 1) Intranasal insulin, or 2) placebo administered with a nasal drug delivery device. We will enroll 40 HIV+ individuals on stable (> 6 months) antiretroviral regimens with cognitive impairment over a 3-year period. Blood tests will include fasting glucose and insulin levels. Neuroimaging markers will include magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI), and arterial spin labeling (ASL) to evaluate neuronal injury, inflammation, and cerebral blood flow. CSF specimens will measure HIV RNA levels, and lipid and protein measures of oxidative stress, and markers of energy metabolism, neuronal injury and immune activation. These combined approaches will examine specific mechanisms of efficacy for CNS protection of intranasal insulin in HIV+ individuals. Outcomes from these studies could have important implications for the design and implementation of future insulin modifying therapies and other neuroprotective compounds for HAND.